ClinVar Genomic variation as it relates to human health

This mutation has been previously reported as disease-causing and was found twice in our laboratory in trans with a missense variant: in an 8-year-old female with low pyruvate dehydrogenase activity, intellectual disability, hearing loss, hypotonia, epilepsy, microcephaly, failure to thrive, hepatopathy, anisocytosis, 2 deceased siblings similarly affected; in a 9-year-old female with spastic quadriparesis, single seizure, failure to thrive, scoliosis. Heterozygotes would be expected to be asymptomatic carriers.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected. (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (101 heterozygotes, 0 homozygotes). (P) 0604 - Variant does not result in the loss of an established domain, motif, hotspot or informative constraint region. (N) 0704 – A comparable truncating variant has low previous evidence for pathogenicity, and has been observed in one family with fatal lactic acidosis (PMID: 27247813). (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with lactic acidosis and Leigh-like disease (ClinVar, PMID: 24341803, PMID: 31042466). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function. Patient fibroblasts were found to have minimal residual protein and reduced lipoyation and mitochondrial respiratory chain protein activity. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Identified in one individual with Leigh syndrome and one individual with seizures, developmental delay and lactic acidemia; both individuals were compound heterozygous for another variant in LIPT1 (Soreze et al. 2013; Ni et al., 2019); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 82 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 28803783, 25326635, 24341803, 29681092, 31042466)

PVS1, PM3

This sequence change creates a premature translational stop signal (p.Ser292*) in the LIPT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the LIPT1 protein. This variant is present in population databases (rs137891647, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with clinical features of lipoyltransferase 1 deficiency (PMID: 24341803, 31042466; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285871). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LIPT1 function (PMID: 31042466). For these reasons, this variant has been classified as Pathogenic.

Variant summary: LIPT1 c.875C>G (p.Ser292X) results in a premature termination codon, predicted to disrupt the last 82 amino acids of the protein. The variant allele was found at a frequency of 0.00036 in 250868 control chromosomes. c.875C>G has been reported in the literature in an individual affected with Leigh disease with hypotonia, tetraparesis and steady aortic root dilatation and in a patient with abnormal development, seizures, and lactic acidemia, both in the compound heterozygous state (Soreze_2013, Ni_2019). Experimental evidence has shown the variant to impact LIPT1 function, including reduced lipoylation of PDHc and -KGDHc, and result in severely decreased PDHc and -KGDHc enzyme activities and abnormal pyruvate utilization by polarography (Soreze_2013, Ni_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31042466, 24341803). ClinVar contains an entry for this variant (Variation ID: 285871). Based on the evidence outlined above, the variant was classified as likely pathogenic.